Supplementary Fig. S1. CONSORT diagram of patient selection and cohort construction. Supplementary Fig. S2. Plasma cell infiltrates before and after NACT. The data was generated and analyzed as in Figure 1. Supplementary Fig. S3. Example of intraepithelial PD-1+ FoxP3+ TIL in a quadruple-color IHC of PD-L1 CD8 PD-1 FoxP3. Supplementary Fig. S4. Unsupervised clustering of TIL based on post-NACT data.
ARTICLE ABSTRACT
Purpose: Some forms of chemotherapy can enhance antitumor immunity through immunogenic cell death, resulting in increased T-cell activation and tumor infiltration. Such effects could potentially sensitize tumors to immunotherapies, including checkpoint blockade. We investigated whether platinum- and taxane-based chemotherapy for ovarian cancer induces immunologic changes consistent with this possibility.Experimental Design: Matched pre- and post-neoadjuvant chemotherapy tumor samples from 26 high-grade serous carcinoma (HGSC) patients were analyzed by immunohistochemistry (IHC) for a large panel of immune cells and associated factors. The prognostic significance of post-chemotherapy TIL patterns was assessed in an expanded cohort (n = 90).Results: Neoadjuvant chemotherapy was associated with increased densities of CD3+, CD8+, CD8+ TIA-1+, PD-1+ and CD20+ TIL. Other immune subsets and factors were unchanged, including CD79a+ CD138+ plasma cells, CD68+ macrophages, and MHC class I on tumor cells. Immunosuppressive cell types were also unchanged, including FoxP3+ PD-1+ cells (putative regulatory T cells), IDO-1+ cells, and PD-L1+ cells (both macrophages and tumor cells). Hierarchical clustering revealed three response patterns: (i) TILhigh tumors showed increases in multiple immune markers after chemotherapy; (ii) TILlow tumors underwent similar increases, achieving patterns indistinguishable from the first group; and (iii) TILnegative cases generally remained negative. Despite the dramatic increases seen in the first two patterns, post-chemotherapy TIL showed limited prognostic significance.Conclusions: Chemotherapy augments pre-existing TIL responses but fails to relieve major immune-suppressive mechanisms or confer significant prognostic benefit. Our findings provide rationale for multipronged approaches to immunotherapy tailored to the baseline features of the tumor microenvironment. Clin Cancer Res; 23(4); 925–34. ©2016 AACR.
